对于绝经后激素受体阳性早期乳腺癌女性，他莫昔芬内分泌辅助治疗2～3年换用芳香酶抑制剂满5年后，延长芳香酶抑制剂内分泌辅助治疗尚有争议。
2017年10月12日，英国《柳叶刀肿瘤学分册》在线发表马斯特里赫特大学、奈梅亨大学、荷兰综合癌症组织、荷兰癌症研究所、凯瑟琳娜医院、莱顿大学、吕伐登医学中心、艾萨拉医院、桑德兰医学中心、海尔德兰谷医院、乌得勒支大学、代芬特尔医院、鹿特丹大学的研究报告，对他莫昔芬→不同持续时间的阿那曲唑治疗进行了评定。
该多中心大样本随机非盲三期前瞻研究（DATA）于2006年6月28日～2009年8月10日在79家荷兰医院进行，筛选他莫昔芬内分泌辅助治疗2～3年后无复发迹象的绝经后激素受体阳性早期乳腺癌女性1912例，按1∶1的比例随机分配，接受3年（955例）或6年（957例）的阿那曲唑治疗，每天1次，每次口服1mg。使用跨欧洲临床研究网络服务（TENALEA）进行随机化步骤。根据淋巴结状态、激素受体状态、HER2状态、他莫昔芬治疗持续时间进行分层分析。该分析主要研究终点为修订无病生存（随机化3年后的无病生存）。本文为DATA研究最终分析报告，该研究已在美国政府临床研究网站（ClinicalTrials.gov）注册，编号：NCT00301457。该研究由阿斯利康提供赞助并参与研究设计。
结果，共有1860例患者符合入组条件（6年组931例，3年组929例），随机分组3年后无病生存1660例，进入主要研究终点分析。
6年组与3年组相比，5年无病生存率相似，复发风险减少21%：
6年组：83.1%（95%CI：80.0～86.3）
3年组：79.4%（95%CI：76.1～82.8）
风险比：0.79（P=0.066）
分层分析表明，对于淋巴结阳性、激素受体双阳性患者，6年组与3年组相比，复发风险分别减少25%、30%（P=0.047、0.011）。
6年组与3年组相比，不良事件发生率较高：
全身关节或肌肉疼痛：58%比53%
骨质减少或骨质疏松：21%比16%
因此，根据该研究结果，不推荐所有绝经后激素受体阳性乳腺癌女性接受他莫昔芬→阿那曲唑5年后继续延长阿那曲唑内分泌辅助治疗，除了淋巴结阳性、激素受体双阳性患者。
对此，加拿大森尼布鲁克健康科学中心和多伦多大学发表同期述评：亚组分析对于延长辅助治疗的意义。
相关阅读
Lancet Oncol. 2017 Oct 12. [Epub ahead of print]
Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial.
Vivianne C G Tjan-Heijnen, Irene E G van Hellemond, Petronella G M Peer, Astrid C P Swinkels, Carolien H Smorenburg, Maurice J C van der Sangen, Judith R Kroep, Hiltje De Graaf, Aafke H Honkoop, Frans L G Erdkamp, Franchette W P J van den Berkmortel, Maaike de Boer, Wilfred K de Roos, Sabine C Linn, Alexander L T Imholz, Caroline M Seynaeve, Dutch Breast Cancer Research Group (BOOG) for the DATA Investigators.
Maastricht University Medical Centre, Maastricht, Netherlands; Radboud University Medical Centre, Nijmegen, Netherlands; Netherlands Comprehensive Cancer Organisation (IKNL), Nijmegen, Netherlands; Antoni van Leeuwenhoek Hospital-Netherlands Cancer Institute, Amsterdam, Netherlands; Catharina Hospital, Eindhoven, Netherlands; Leiden University Medical Center, Leiden, Netherlands; Medical Centre Leeuwarden, Leeuwarden, Netherlands; Isala Clinics, Zwolle, Netherlands; Zuyderland Medical Center Heerlen-Sittard-Geleen, Sittard-Geleen, Geleen, Netherlands; Zuyderland Medical Center Heerlen-Sittard-Geleen, Heerlen, Netherlands; Gelderse Vallei Hospital, Ede, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands; University Medical Centre Utrecht, Netherlands; Deventer Hospital, Deventer, Netherlands; Erasmus MC Cancer Institute, Rotterdam, Netherlands.
BACKGROUND: The effect of extended adjuvant aromatase inhibition in hormone receptor-positive breast cancer after sequential endocrine therapy of tamoxifen followed by an aromatase inhibitor for a 5-year treatment period still needs clarification. To address this issue, we began the DATA study to assess different durations of anastrozole therapy after tamoxifen.
METHODS: DATA was a prospective, randomised, open-label, multicentre, phase 3 study done in 79 hospitals in the Netherlands. We randomly assigned postmenopausal women with hormone receptor-positive early breast cancer with no signs of disease recurrence after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole treatment (1 mg orally once a day) in a 1:1 ratio. We used TENALEA (Trans European Network for Clinical Trials Services) for the randomisation procedure. Stratification factors were nodal status, hormone receptor status, HER2 status, and tamoxifen treatment duration. The primary study endpoint of this analysis was disease-free survival starting beyond 3 years after randomisation (adapted disease-free survival). Here we report the final analysis from the DATA trial, which is registered with ClinicalTrials.gov, number NCT00301457.
FINDINGS: Between June 28, 2006, and Aug 10, 2009, we screened 1912 patients of whom 955 were assigned to the 3-year group and 957 to the 6-year anastrozole treatment group. 1860 patients were eligible (931 in the 6-year group and 929 in the 3-year group) and 1660 were disease free 3 years after randomisation. The 5-year adapted disease-free survival was 83.1% (95% CI 80.0-86.3) in the 6-year group and 79.4% (76.1-82.8) in the 3-year group (hazard ratio [HR] 0.79 [95% CI 0.62-1.02]; p=0.066). Patients in the 6-year treatment group had more adverse events than those in the 3-year treatment group, including all-grade arthralgia or myalgia (478 [58%] of 827 in the 6-year treatment group vs 438 [53%] of 833 in the 3-year treatment group) and osteopenia or osteoporosis (173 [21%] vs 137 [16%]).
INTERPRETATION: We cannot recommend the use of extended adjuvant aromatase inhibition after 5 years of sequential endocrine therapy in all postmenopausal women with hormone receptor-positive breast cancer.
FUNDING: AstraZeneca.
DOI: 10.1016/S1470-2045(17)30600-9
Lancet Oncol. 2017 Oct 12. [Epub ahead of print]
Extended adjuvant therapy: the role of subset analyses.
Kathleen I Pritchard.
Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
The report of the DATA trial[1] by Vivianne Tjan-Heijnen and colleagues and published in The Lancet Oncology adds to the current body of information delineating the role of extended adjuvant aromatase inhibition in women already treated with tamoxifen followed by an aromatase inhibitor. Women were randomly assigned to treatment after 2-3 years of treatment with adjuvant tamoxifen to either 3 or 6 years of further anastrozole treatment with a primary study endpoint of disease-free survival. Since women in both study groups had a common initial 3-year period of anastrazole treatment, the analysis presented started 3 years after randomisation and is described by the authors as an adapted disease-free survival analysis.
The authors report a hazard ratio of 0.79 (95% CI 0.62-1.02; p=0.066) for 5-year adapted disease-free survival with the use of 3 additional years of anastrazole, which was technically—as they correctly report—a negative overall finding. They also report that two post-hoc subset analyses, one for patients with both positive oestrogen and positive progesterone receptors, and one for patients who received chemotherapy, might suggest efficacy of the extra 3-year treatment for these selected groups of patients.
In fact, the overall trial results, particularly in the setting of several other trials addressing the same question[2-4], could be interpreted as representing a positive signal. The DATA results are consistent with most, if not all, of the available published or presented literature, which includes results that have a significantly positive outcome[2], are indicative of a positive outcome[3], or are neutral[4]. However, the interpretation of the two subset analyses in DATA with tests of interaction, which are also negative, is likely to be overly positive.
Great care must be taken when interpreting subset analyses in clinical trials. Although DATA is quite a large study with 1660 eligible patients and 261 recurrences, the number of events for any subgroup analysis becomes perilously small. It is most appropriate in such situations to prespecify what subset analyses will be done, to give priority to analyses regarding factors for which the randomisation is stratified, to test for interaction factors among subset outcomes, and to apply a stiff correction factor to the p values acquired. Additionally, these subset analyses should be interpreted as hypothesis generating, rather than definitive.
The DATA subset analysis of those who received or did not receive chemotherapy was not prespecified and not based on a stratification factor but might have some plausible rationale. Furthermore, similar results for this subset have been suggested by others[2]. The subset analysis by oestrogen or progesterone receptor status is based on a stratification factor and one for which there is biological plausibility to postulate interaction with the randomly allocated therapies. These tests for interaction, which have produced p values of 0.077 (for the use of chemotherapy) and 0.078 (for oestrogen and progesterone receptor status) have, appropriately, been quite conservatively reported and discussed by the authors. However, they do mention in the discussion the possibility of analyses of even smaller subsets such as patients with positive oestrogen receptor status, positive progesterone receptor status, and node-positive disease, or with a large tumour size. Here, even more caution must be advised for fear of over-interpreting these tempting but perhaps misleading subset analyses.
And where do the results of this trial take us in terms of today's clinical practice? The DATA trial adds to an increasing body of information supporting the use of aromatase inhibitors beyond 2-5 years, much of it from trials including patients who have previously received 2-5 years of tamoxifen[2-4]. There are some—but not as much—data available regarding longer aromatase inhibitor therapy in women who had not previously received tamoxifen[2-5], but this too suggests that longer therapy is better. Of course, as briefly reported here, increasing length of treatment is also associated with increased side-effects, which include arthralgia or myalgia and osteoporosis or fractures[1,2,6]. Furthermore, as has been seen in other trials[2,3,5], much of the effect of longer adjuvant aromatase inhibitor therapy is comprised of a reduction in the number of contralateral breast cancers, which is not likely to be as directly linked to overall survival as are reductions in distant or even loco-regional recurrences.
Therefore, as is often the case, today's clinician is forced to advise and treat patients with less complete information than they might wish to have. However, it is becoming increasingly clear that a longer duration of aromatase inhibitor therapy improves outcomes and can be recommended to women, particularly those who have had previous tamoxifen therapy, together with an explanation of the possible side-effects that might occur. What is much less clear is which, or indeed if, different subsets of women receive less or more benefit from extended therapy with aromatase inhibitors. In fact, a recent meta-analysis[7] found that no significant difference in benefits could be detected for any of the subsets explored. Such differing subset benefits were initially suggested for adjuvant aromatase inhibitors by comparison with adjuvant tamoxifen, but when all the data were combined in a patient based meta-analysis, there was no significant interaction with treatment for any of these subsets[8].
In summary, this well done and mature trial adds considerably to the body of data examining the important question of optimal duration of adjuvant endocrine therapy. However, overly enthusiastic subset analyses by either authors or readers should not be allowed to distract from the main message. It is to be hoped that when the results of additional studies of similar design to DATA such as LATER (ACTRN12607000137493), N-SAS-BC-05 (UMIN000000818), and MINDACT (NCT00433589) become available, comparisons between studies and appropriate meta-analyses might help to more accurately identify any robust predictive factors that will help us to personalise these therapies. In the meantime, extrapolating clinical conclusions from underpowered subset analyses should be avoided.
REFERENCES
Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, et al. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. Lancet Oncol. 2017 Oct 12. DOI: 10.1016/S1470-2045(17)30600-9. [Epub ahead of print]
Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375(3):209-219.
Mamounas E, Bandos H, Lembersky B, et al. A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor (AI): Results from NRG Oncology/NSABP B-42. Cancer Res. 2017;77(4 Suppl):S1-05. DOI:10.1158/1538-7445.SABCS16-S1-05
Blok E, van de Velde C, Meershoek-Klein Kranenbarg E, et al. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05). Cancer Res. 2017;77(4 Suppl):S1-04. DOI: 10.1158/1538-7445.SABCS16-S1-04
Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007;99(24):1845-1853.
Goldvaser H, Barnes TA, Seruga B, et al. Toxicity of extended adjuvant therapy with aromatase inhibitors in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2018;110(1):djx141.
Goldvaser H, AlGorashi I, Ribnikar D, et al. Efficacy of extended adjuvant therapy with aromatase inhibitors in early breast cancer among common clinicopathologically-defined subgroups: a systematic review and meta-analysis. Cancer Treat Rev. 2017;60:53-59.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352.
DOI: 10.1016/S1470-2045(17)30787-8
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